CN1753661A - Adenosine a1 receptor antagonist for the treatment of cardiac and renal diseases - Google Patents

Abstract

Disclosed are pharmaceutical composition comprising a beta-blocker and an adenosine A1 receptor antagonist (AA1RA), an angiotensin converting enzyme (ACE) inhibitor and an adenosine A1 receptor antagonist (AA1RA), and an angiotensin II receptor blocker (ARB) and an adenosine A1 receptor antagonist (AA1RA). Also disclosed are methods of treating cardiovascular disease, renal disease, alkalosis, or diabetic nephropathy comprising identifying a patient in need of such treatment, and administering a pharmaceutical composition disclosed herein to said patient.

Description

Adenosine A1 receptor antagonists for the treatment of heart and kidney diseases

related application

This patent application claims the title "Use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers with adenosine A1 receptor antagonists and beta-blockers" filed on February 24, 2003 by Dittrich et al. No. 60/449,953 U.S. Provisional Patent No. 2, 449,953 U.S. Provisional No. 60/450,499, filed on the 25th, entitled "METHOD OF TREATMENT OFDISEASE USING AN ADENOSINE A1 RECEPTOR ANTAGONIST AND ABETA-BLOCKER" Patent application; Dittrich et al. on February 25, 2003 entitled "USE OF ADENOSINE A1 RECEPTOR ANTAGONISTS IN PRE-DIABETICPATIENTS IN PRE-DIABETICPATIENTS AND EARLY DIABETES MELLITUS FOR THE PREVENTION OF DIABETICNEPHORPATHY), U.S. Provisional Patent Application No. 60/450,500; Dittrich et al., filed Feb. 28, 2003, entitled "Method of Treating Alkalosis Using an Adenosine A1 Receptor Antagonist" ( METHOD OF TREATINGALKALOSIS USING ADENOSINE A1 RECEPTOR ANTAGONISTS) U.S. Provisional Patent Application No. 60/451,326; Dittrich et al., filed April 21, 2003, entitled "Method of Treating Alkalosis Using Adenosine A1 Receptor Antagonists" (METHOD OF TREATING ALKALOSIS USING ADENOSINE A1 RECEPTORANTAGONISTS) U.S. Provisional Patent Application No. 60/464,811; Dittrich et al., filed April 21, 2003, entitled "Use of angiotensin-converting Method for Treating Diseases with Adenosine A1 Receptor Antagonists and β-Blockers" (METHOD OF TREATMENT OFDISEASE USING AN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANANGIOTENSIN II RECEPTOR BLOCKER AND AN ADENOSINE A1 RECEPTORANTAGONIST AND A BETA-BLOCKER) U.S. Provisional Patent Application No. 464,812; Dittrich et al., entitled "Use of Adenosine A1 Receptor Antagonists in Prevention of Diabetic Nephropathy in Prediabetes and Early Diabetes" on April 21, 2003 RECEPTORANTAGONISTS IN PRE-DIABETIC PATIENTS AND EARLY DIABETES MELLITUSFOR THE PREVENTION OF DIABETIC NEPHORPATHY) U.S. Provisional Patent Application No. 60/464,813; and Dittrich et al. Priority of U.S. Provisional Patent Application No. 60/464,815 for METHOD OF TREATMENT OF DISEASE USING ANADENOSINE A1 RECEPTOR ANTAGONIST AND A BETA-BLOCKER; the full text of all provisional patent applications is incorporated by reference way incorporated into this article.

technical field

The present invention relates to a pharmaceutical composition comprising an adenosine A1 receptor antagonist alone or in combination with other drugs, and a method of treating patients suffering from heart disease and/or renal failure with said composition.

Background technique

Contents of the invention

The present invention discloses a _{pharmaceutical} composition comprising a beta-blocker and an adenosine A ₁ receptor antagonist (AA ₁ RA).

In addition, the present invention discloses a pharmaceutical composition comprising an angiotensin converting enzyme (ACE) inhibitor and an adenosine A ₁ receptor antagonist (AA ₁ RA).

In addition, the present invention discloses a pharmaceutical composition comprising an angiotensin II receptor blocker (ARB) and an adenosine A ₁ receptor antagonist (AA ₁ RA).

The present invention also discloses a method of treating cardiovascular disease or renal disease comprising determining a patient in need of such treatment, and administering to said patient a pharmaceutical composition disclosed herein.

Disclosed herein are methods of treating alkalosis comprising determining that a patient is in need of such treatment, and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). The present invention also discloses pharmaceutical compositions comprising _AAiRA .

Disclosed herein are methods of treating diabetic nephropathy comprising determining that a patient is in need of such treatment, and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). The present invention also discloses pharmaceutical compositions comprising _AAiRA .

Detailed ways

AA ₁ RA

Aspects of the present disclosure relate to methods of using _AAiRAs alone or in combination with one or more other pharmaceutical agents to treat various diseases. Although many _AAiRAs are not currently commercially available as therapeutics, they are known in the art. AA ₁ RAs selectively antagonize the A ₁ receptors for adenosine. Most known AA ₁ RAs are derivatives of xanthines and include, for example, 1,3-dipropyl-8-{3-oxatricyclo[ ^3.1.2.0.2,4 ]octyl-6(7)- Base}xanthine (1,3-dipropyl-8-{3-oxatricyclo[ ^3.1.2.0.2,4 ]oct-6(7)-yl}xanthine) (also known as 1,3-dipropyl-8 -[5,6-exo-epoxy-2(S)norbornyl]xanthine (1,3-dipropyl-8-[5,6-exo-epoxy-2(S)norbornyl]xanthine), ENX, CVT-124 and BG9719), 8-(3-noradamantyl)-1,3-dipropylxanthine (8-(3-noradamantyl)-1,3-dipropylxanthine) (also known as KW-3902) , theophylline and caffeine compounds. Other AA ₁ RAs are disclosed in US Patent Nos. 5,446,046, 5,631,260, and 5,668,139, the entire specifications of all patents, including all figures, are incorporated herein by reference. The scope of the present invention includes all those currently known _AA1RAs and all those _AA1RAs to be discovered in the future.

The _AAiRA used in the pharmaceutical compositions or methods disclosed herein can be a xanthine derivative compound. The xanthine derivative compound can be a compound of formula I or a pharmaceutically acceptable salt thereof,

in

X ₁ and X ₂ each independently represent oxygen or sulfur;

Q means:

或

or

Wherein Y represents a single bond or an alkylene group with 1 to 4 carbon atoms, and n represents 0 or 1;

R _and R _each independently represent hydrogen, lower alkyl, allyl, propargyl, or hydroxy-substituted, oxygen-substituted or unsubstituted lower alkyl, and _R represents hydrogen or lower alkyl, or

R ₄ and R ₅ are the same or different and each represents hydrogen or hydroxyl, and when R ₄ and R ₅ are both hydrogen, at least one of R ₁ and R ₂ is a hydroxyl-substituted or oxygen-substituted lower alkyl group,

But when Q is

, then R ₁ , R ₂ and R ₃ are not methyl at the same time.

In some embodiments, R ₁ and R ₂ in the compound of formula I are both lower alkyl and R ₃ is hydrogen; and X ₁ and X ₂ are both oxygen. In other embodiments, R ₁ , R ₂ and R ₃ independently represent hydrogen or lower alkyl. In still other embodiments, R ₁ and R ₂ each independently represent allyl or propargyl and R ₃ represents hydrogen or lower alkyl. In certain embodiments, X ₁ and X ₂ are both oxygen and n is 0.

In some embodiments, R ₁ is hydroxy-substituted, oxo-substituted or unsubstituted propyl; R ₂ is hydroxy-substituted or unsubstituted propyl; and Y is a single bond. In other embodiments, R ₁ is propyl, 2-hydroxypropyl, 2-oxopropyl or 3-oxopropyl; R ₂ is propyl, 2-hydroxypropyl or 3-hydroxypropyl.

在其他实施例中，Q为9-羟基、9-氧代或6-羟基取代3-三环[3.3.1.0^3，7]壬基(3tricyclo[3.3.1.0^3，7]nonyl)或3-羟基-1-三环[3.3.1.1^3，7]癸基(3-hydroxy-ltricyclo[3.3.1.1^3，7]decyl)。In some embodiments, Q is While in other embodiments, Q is

In other embodiments, Q is 9-hydroxyl, 9-oxo or 6-hydroxyl substituted 3-tricyclo[3.3.1.0 ^3,7 ]nonyl (3tricyclo[3.3.1.0 ^3,7 ]nonyl) or 3- 3-hydroxy-ltricyclo[3.3.1.1 ^{3,7 ]} decyl.

In certain embodiments, the AA ₁ RA is selected from the group consisting of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (8-(noradamantan-3 -yl)-1,3-dipropylxanthine), 1,3-diallyl-8-(3-noradamantyl)xanthine (1,3-Diallyl-8-(3-noradamantyl)xanthine), 3 -Allyl-8-(3-noradamantyl)-1-propargylxanthine (3-allyl-8-(3-noradamantyl)-1-propargylxanthine), 8-(trans-9-hydroxy- 3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1 , 3-dipropylxanthine), 8-(cis-9-hydroxyl-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine (8-(cis-9-hydroxy- 3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine), 8-(trans-9-hydroxyl-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1-(2 -Oxopropyl)-3-propylxanthine (8-(trans-9-hydroxy-3-tricyclo[ ^3.3.1.03,7 ]nonyl-1-(2-oxopropyl)-3-propylxanthine) and 1 -(2-hydroxypropyl)-8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-3-propylxanthine (1-(2-hydroxypropyl)-8 -(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-3-propylxanthine), or a pharmaceutically acceptable salt thereof.

In other embodiments, the AA ₁ RA is a xanthine epoxy derivative compound of formula II or formula III, or a pharmaceutically acceptable salt thereof,

Wherein R ₆ and R ₇ are the same or different, and can be hydrogen or a group of alkyl groups with 1 to 4 carbon atoms, R ₈ is oxygen or (CH ₂ ) _1-4 , and n=0-4.

The xanthine epoxy derivative compound can be

或

or

Combination with beta-blockers

Aspects of the invention relate to the treatment of cardiovascular disease using a beta-blocker in combination with an adenosine _A1 receptor antagonist (or _AA1RA ). Each of these compounds has individually been shown to be somewhat effective in the treatment of cardiovascular diseases such as congestive heart failure, hypertension, asymptomatic left ventricular dysfunction or coronary artery disease.

Many beta-blockers are commercially available. These compounds include, but are not limited to, acebutolol hydrochloride, atenolol, betaxolol hydrochloride, bisoprolol fumarate, carteolol hydrochloride carteolol hydrochloride, esmolol hydrochloride, metoprolol, metoprolol tartrate, nadolol, penbutolol sulfate ), pindolol, propranolol hydrochloride, succinate and timolol maleate. Beta-blockers are generally beta ₁ and/or beta ₂ adrenoceptor blockers, which reduce the positive chronotropic, positive inotropic, bronchodilation, and vascular effects induced by beta adrenoceptor agonists Expansion response. The scope of the present invention includes all those currently known beta-blockers and all those beta-blockers to be discovered in the future.

An important problem encountered in the treatment of certain conditions with a single drug is that the patient becomes refractory to treatment after a period of time, ie the patient begins to respond less and less to the drug or not at all. This problem is very common in patients with, for example, congestive heart failure treated with diuretics.

Individual diuretics act on a specific part of the nephron, such as the proximal tubule, the loop of Henle, or the distal tubule. One mechanism by which diuretics increase urine output is their inhibition of sodium and concomitant reabsorption of water through the nephron. Thus, for example, loop diuretics inhibit resorption in the loop of Henle. As a result, higher concentrations of sodium flow down the distal tubule. Initially this results in more urine output and therefore has a diuretic effect. However, the distal portion of the tubule recognizes the increase in sodium concentration and the kidney responds in two ways: one by increasing sodium reabsorption elsewhere in the nephron; the other by feeding back input through the adenosine _A1 receptor Small arteries, where vasoconstriction occurs. This feedback mechanism is called tubuloglomerular feedback (TGF). This vasoconstriction results in a decrease in renal blood flow and a decrease in glomerular filtration rate (GFR). Over time, these two mechanisms lead to decreased diuresis and worsening of renal function. This sequence of several phenomena drives the development of the disease.

The present inventors have discovered that the combination of _AAiRA and a beta-blocker is beneficial for congestive heart failure (CHF) or hypertension, or any of the other conditions described herein. Beta-blockers are known to have antihypertensive effects. Although the exact mechanism of their action is unknown, possible mechanisms have been proposed, such as decreased cardiac output, decreased plasma renin activity, and central nervous system antisympathetic effects. According to various clinical studies, administration of beta-blockers to hypertensive patients apparently initially results in a decrease in cardiac output, a small immediate change in blood pressure and an increase in calculated peripheral resistance. With continued dosing, blood pressure decreased over several days, cardiac output remained low and peripheral resistance decreased to pre-treatment levels. Plasma renin activity is also markedly reduced in hypertensive patients, which would have an inhibitory effect on the renin-angiotensin system, thereby reducing afterload and enabling a more effective promotion of cardiac function. The use of these compounds has been shown to increase survival in patients with CHF or hypertension. Said compounds are now part of the standard medicines for the treatment of CHF and hypertension.

_AAiRA acts on the renal afferent arterioles in CHF patients, producing vasodilation and thus improving renal blood flow. They also block the TGF mechanism mediated by adenosine (via the _A1 receptor) as described above. This ultimately results in increased GFR and improved renal function. In addition, _AAiRA inhibits the reabsorption of sodium (and thus water) in the proximal tubule, which results in diuresis.

The combinations of the invention described herein act synergistically to further improve the condition of hypertensive or CHF patients. Particularly in salt-sensitive hypertensive patients, the diuretic effect of AA ₁ RA together with blockade of β-adrenergic receptors lowers blood pressure through two different mechanisms, their actions building on each other. In addition, most CHF patients also require additional diuretics. By improving renal blood flow and renal function, the combination allows for greater efficacy of other more distally acting diuretics.

Beta-blockers are well established in the treatment of hypertension. The addition of _AAiRA will further treat hypertension through its diuretic effect which inhibits the reabsorption of sodium flowing through the proximal tubule. In addition, since many hypertensive patients are sodium sensitive, adding _AAiRA to a beta-blocker will result in a further decrease in blood pressure. The action of AA ₁ RA on tubuloglomerular feedback will further improve renal function leading to stronger diuresis and lower blood pressure.

Accordingly, one aspect of the present disclosure relates to a pharmaceutical composition comprising a beta-blocker and an adenosine _A1 receptor antagonist ( _AA1RA ). The beta-blocker may be selected from the group consisting of: acebutolol hydrochloride, atenolol, betaxolol hydrochloride, bisoprolol fumarate, carteolol hydrochloride, ixacin hydrochloride Smolol, metoprolol, metoprolol tartrate, nadolol, pembrolol sulfate, pindolol, propranolol hydrochloride, succinate, and timolol maleate, or A pharmaceutically acceptable salt, prodrug, ester or amide thereof. However, it is also within the scope of the invention to include other beta-blockers.

Another aspect of the disclosure relates to a method of treating cardiovascular or renal disease comprising determining a patient in need of such treatment, and administering to said patient a pharmaceutical composition described herein. In certain embodiments, the patient may be a mammal, and the mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, Sheep, goats, cows, primates (such as monkeys, chimpanzees and apes) and humans. In some embodiments, the patient is human.

In some embodiments, the administering step comprises administering said β-blocker and said AA ₁ RA substantially simultaneously. These embodiments include those in which the AA ₁ RA and the beta-blocker are in the same administrable composition, i.e. a single tablet, pill or capsule containing both compounds, or a single intravenous solution, or A single drinkable solution, or a single sugar-coated formulation or ointment. The examples also include examples where each compound is in a composition that can be administered separately, but the patient is instructed to take the separate compositions at about the same time, i.e. immediately after taking one pill or after injecting one A compound is injected immediately after another compound, etc.

In other embodiments, the administering step comprises first administering one of the beta-blocker and _AAiRA and then administering the other of the beta-blocker and _AAiRA . In these embodiments, the patient may be administered a composition comprising one of the compounds, followed by another combination comprising the other of the compounds some time later (minutes or hours) things. Also included within these embodiments are embodiments in which a patient is administered a composition comprising one of the compounds on a routine or continuous basis while occasionally receiving a composition comprising the other compound.

The methods of the present invention are intended to provide treatment for cardiovascular disease, which may include congestive heart failure, hypertension, asymptomatic left ventricular dysfunction, atrial fibrillation, arrhythmias refractory to other modality, recurrent Ventricular tachycardia, recurrent ventricular fibrillation, coronary artery disease, or acute myocardial infarction. In some cases, patients with cardiovascular disease require afterload reduction. The methods of the invention are also suitable for providing treatment for these patients.

Another aspect of the present invention relates to a pharmaceutical composition comprising a combination of AA ₁ RA as described above and a beta-blocker, and a physiologically acceptable carrier, diluent or excipient or a combination thereof .

Combination with ACE inhibitors or angiotensin II receptor blockers

Aspects of the invention relate to the use of an adenosine _A1 receptor antagonist (or _AA1RA ) in combination with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) to treat renal and /or heart disease. In cardiac disease such as congestive heart failure, hypertension, asymptomatic left ventricular dysfunction or acute myocardial infarction or such as diabetic nephropathy, contrast agent-mediated nephropathy, toxin-induced renal injury or oxygen free radical mediated nephropathy Each of these compounds has been shown to be somewhat effective individually in the treatment of kidney disease in the United States.

Many ACE inhibitors are commercially available. Compounds with somewhat similar chemical structures include lisinopril, enalapril, quinapril, ramipril, benazepril, Cato captopril, fosinopril, moexipril, trandolapril, and perindopril. ACE inhibitors are generally compounds that inhibit the action of angiotensin-converting enzyme, which converts angiotensin I to angiotensin II. The scope of the present invention includes all those currently known ACE inhibitors and all those ACE inhibitors to be discovered in the future.

Many ARBs are also commercially available or known in the art. These compounds include losartan, irbesartan, candesartan, telmisartan, eposartan, and valsartan. ARBs lower blood pressure by relaxing blood vessels. This allows for better blood flow. The function of ARBs stems from their ability to block the binding of angiotensin II, which normally causes vasoconstriction. The scope of the present invention includes all those currently known ARBs and all those ARBs to be discovered in the future.

The present inventors have found that the combination of _AAiRA with an ACE inhibitor or ARB is beneficial in congestive heart failure (CHF) or hypertension. The use of ACE inhibitors and ARBs in CHF is dependent on inhibition of the renin-angiotensin system. These compounds reduce afterload, thereby allowing more effective stimulation of cardiac function. Additionally, kidney function is "normalized" or improved so that the patient can more effectively eliminate excess fluid. The use of these compounds has been shown to increase survival in patients with CHF or hypertension. Said compounds are now part of the standard medicines for the treatment of CHF and hypertension.

The combinations of the invention described herein act synergistically to further improve renal function for sustained diuresis. In addition, most CHF patients also require additional diuretics. The combination enables greater efficacy of other more distally acting diuretics by improving renal blood flow and renal function.

Both ACE inhibitors and ARBs are well established in the treatment of hypertension acting through the renin-angiotensin system. The addition of _AAiRA will further treat hypertension through its diuretic effect which inhibits the reabsorption of sodium flowing through the proximal tubule. In addition, since many hypertensive patients are sodium sensitive, the addition of _AAiRAs to ACE inhibitors or ARBs will result in a further reduction in blood pressure. AA ₁ RA acting on the glomerular feedback further improves renal function leading to stronger diuresis and lower blood pressure.

ACE inhibitors and ARBs are also known to prevent renal injury induced by the immunosuppressant, cyclosporin A. However, although they are available, there are renal damage effects. The present inventors have found that ACE inhibitors and ARBs in combination with _AA1RA will be more effective in preventing drug-induced nephrotoxicity, such as that induced by cyclosporin A, (iodinated) contrast agents and aminoglycoside antibiotics . In this context there is renal vasoconstriction which can be minimized by both compounds. In addition, the direct negative effect of cyclosporin on renal tubular epithelial cells was less pronounced in the presence of an adenosine _A1 receptor antagonist, in which _A1 receptors reduce the active process of blocking. In addition, there are fewer oxidative byproducts that are detrimental to renal tubular epithelial cells. In addition, the inhibition of tubulobulbar feedback mechanisms by AA ₁ RA blockade contributes to preservation of function in the presence of nephrotoxic drugs.

ACE inhibitors and ARBs are known to be beneficial in preventing exacerbation of renal dysfunction in diabetic patients as measured by proteinuria. Once diabetes begins, glycosuria develops and the kidneys begin to actively reabsorb glucose, especially through the proximal convoluted tubule. This active process can lead to oxidative stress and initiate the disease process of diabetic nephropathy. Early in this process manifested as renal hypertrophy and renal hyperplasia. Eventually, the kidneys begin to show other symptoms, such as microalbuminuria and diminished kidney function. hypothesized that the active reabsorption of glucose is regulated in part through the adenosine _A1 receptor. Blocking this process by _AA1RA would limit or prevent the early damage seen in diabetic patients.

Combinations of _AAiRAs with ACE inhibitors or ARBs as disclosed herein act to limit early and secondary damage to the kidneys in diabetic patients. The combinations disclosed in the present invention are administered at the time of diagnosis of diabetes or as soon as glycosuria is detected in at-risk patients (metabolic syndrome). Long-term treatment with the combinations of the present invention involves daily administration of the pharmaceutical compositions described herein.

Thus, in one aspect the present invention relates to a pharmaceutical composition comprising an angiotensin converting enzyme (ACE) inhibitor and an adenosine A ₁ receptor antagonist (AA ₁ RA). The ACE inhibitor may be selected from the group consisting of lisinopril, enalapril, quinapril, ramipril, benazepril, captopril, fosinopril , moexipril, trandolapril and perindopril, or pharmaceutically acceptable salts, prodrugs, esters or amides thereof. However, it is also within the scope of the invention to include other ACE inhibitors.

Another aspect of the present invention relates to a pharmaceutical composition comprising an angiotensin II receptor blocker (ARB) and an adenosine A ₁ receptor antagonist (AA ₁ RA). The ARB may be selected from the group consisting of losartan, irbesartan, candesartan, telmisartan, eposartan, and valsartan, or a pharmaceutically acceptable salts, prodrugs, esters or amides. However, it is within the scope of the invention to include other ARBs.

Another aspect of the present invention relates to a pharmaceutical composition comprising an ACE inhibitor, an ARB and an adenosine A ₁ receptor antagonist (AA ₁ RA).

Another aspect of the invention relates to a method of treating cardiovascular disease or renal disease comprising determining that a patient is in need of said treatment, and administering to said patient a pharmaceutical composition as described herein. In certain embodiments, the patient may be a mammal, and the mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, Sheep, goats, cows, primates (such as monkeys, chimpanzees and apes) and humans. In some embodiments, the patient is human.

In some embodiments, the administering step comprises administering said ACE inhibitor or said ARB and said _AAiRA substantially simultaneously. These embodiments include those in which the AA ₁ RA and the ACE inhibitor or ARB are in the same administrable composition, i.e. a single tablet, pill or capsule containing both compounds, or a single intravenous solution, or a single intravenous solution. A single drinkable solution, or a single sugar-coated formulation or ointment. The examples also include examples where each compound is in a composition that can be administered separately, but the patient is instructed to take the separate compositions at about the same time, i.e. immediately after taking one pill or after injecting one A compound is injected immediately after another compound, etc.

In other embodiments, the administering step comprises first administering the ACE inhibitor or the one of the ARB and the _AAiRA followed by administering the other of the ACE inhibitor or the ARB and the _AAiRA . In these embodiments, the patient may be administered a composition comprising one of the compounds, followed by another combination comprising the other of the compounds some time later (minutes or hours) thing. Also included within these embodiments are embodiments in which a patient is administered a composition comprising one of the compounds on a routine or continuous basis while occasionally receiving a composition comprising the other compound.

The methods of the present invention are intended to provide treatment for cardiovascular disease, which may include congestive heart failure, hypertension, asymptomatic left ventricular dysfunction, or acute myocardial infarction. In some cases, patients with cardiovascular disease require afterload reduction. The methods of the invention are also suitable for providing treatment for these patients.

The methods of the present invention are also intended to provide treatment for renal disease, which may include renal hypertrophy, renal hyperplasia, microalbuminuria, proteinuria, diabetic nephropathy, contrast agent-mediated nephropathy, toxin-induced renal damage, or oxygen free radical mediated nephropathy, hypertensive nephropathy, diabetic nephropathy, contrast agent-mediated nephropathy, toxin-induced renal injury or oxygen free radical-mediated nephropathy.

Another aspect of the present invention relates to a pharmaceutical composition comprising a combination of _AA1RA as described above and an ACE inhibitor or ARB, and a physiologically acceptable carrier, diluent or excipient or a combination thereof .

Alkalosis treatment

Alkalosis is an acid-base balance disorder caused by elevated plasma bicarbonate (HCO ₃ ^- ) concentration. It is a primary pathophysiological event characterized by gain of bicarbonate or loss of fixed acid from extracellular fluid. The kidney maintains normal acid-base balance through two mechanisms: recycling of bicarbonate, primarily in the proximal tubule, and production of bicarbonate, primarily in the distal nephron. Bicarbonate recycling is mainly regulated by the Na ⁺ -H ⁺ antiporter and to a lesser extent by the adenosine triphosphate enzyme (H ⁺ -ATPase). The main factors affecting HCO ₃ ^{-reabsorption} include effective arterial blood volume, glomerular filtration rate, potassium, and partial pressure of carbon dioxide. Bicarbonate regeneration is primarily influenced by distal ^Na delivery and reabsorption, aldosterone, systemic pH, ammonium excretion, and titratable acid excretion.

There are many different types of alkalosis, such as metabolic alkalosis and respiratory alkalosis. Respiratory alkalosis is a condition that affects climbers at high altitudes.

For metabolic alkalosis to occur, either a base gain or an acid loss must occur. Acid loss can be through the upper gastrointestinal tract or through the kidneys. Excess base can ^be obtained by oral or parenteral administration of _HCO3- , or by administration of lactate, acetate or citrate.

Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate, volume contraction, hypokalemia, and excess aldosterone. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid overdose, adrenogenital syndrome, licorice ingestion, administration of diuretics, and Bartter's and Gitelman's syndromes.

The two types of metabolic alkalosis (ie, chloride-responsive and chloride-resistant) are classified according to the amount of chloride in the urine. Chloride-responsive metabolic alkalosis involves urinary chloride levels below 10 milliequivalents per liter (mEq/L) and is characterized by decreased extracellular fluid (ECF) volume and low serum chloride, if associated with vomiting occur. This type responds to administration of chloride salts. Chloride-resistant metabolic alkalosis involves urinary chloride levels above 20 mEq/L and is characterized by increased ECF volume. As the name implies, this type resists the administration of chloride salts. Excessive oral base intake (usually milk plus calcium carbonate) and alkalosis complicated by primary aldosteronism are examples of chloride-resistant alkalosis.

Many patients with edematous conditions are treated with diuretics. Unfortunately, with continued therapy, the patient's bicarbonate levels increase and progressive alkalosis may ensue. Diuretics cause metabolic alkalosis through several mechanisms, including (1) acute contraction of extracellular fluid (ECF) volume (excretion of NaCl but not HCO ₃ ^- ), thereby increasing the concentration of HCO ₃ ^- in the ECF; (2) diuresis drug-induced potassium and chloride depletion; and (3) secondary aldosteronism. Continued use of diuretics or either of the latter two factors will maintain alkalosis.

Addition of AA ₁ RA allows continued diuresis and maintenance of renal function without exacerbating alkalosis. AA ₁ RA inhibits active reabsorption of HCO ₃ ^- through renal proximal tubules.

Thus, in one aspect the invention relates to a method of treating metabolic alkalosis comprising determining that a patient is in need of said treatment and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). In certain embodiments, the patient suffers from high altitude mountain sickness. In some embodiments, the patient has edema. In some of these embodiments, the patient may be on diuretic therapy. The diuretic may be a loop diuretic, a proximal diuretic, or a distal diuretic. In other embodiments, the patient is experiencing acid loss through the patient's upper gastrointestinal tract, eg, through excessive emesis. In yet other embodiments, the patient ingests an excess of oral base. The methods of the present invention can be practiced with any compound that antagonizes the adenosine _A1 receptor.

Another aspect of the present invention relates to a pharmaceutical composition comprising the AA ₁ RA combination as described above, and a physiologically acceptable carrier, diluent or excipient or a combination thereof.

Treatment of Diabetic Nephropathy

Uncontrolled diabetes can cause damage to many tissues in the body. Much of the kidney damage caused by diabetes often involves thickening and hardening of the internal kidney structures, especially the glomeruli (renal membranes). Kimmelstiel-Wilson disease is a unique microscopic feature of diabetic nephropathy in which sclerosis of the glomeruli is accompanied by vitreous nodular deposits.

The glomerulus is where blood is filtered and urine is formed. It acts as a selective membrane, allowing some substances to be excreted into the urine and others to remain in the body. As diabetic nephropathy progresses, an increasing number of glomeruli are destroyed, resulting in weakened kidney function. Protein that is slowed down by filtration and normally kept in the body (ie, albumin) may leak into the urine. Albumin can appear in the urine for 5 to 10 years before other symptoms develop. Diabetic nephropathy is often accompanied by hypertension.

Diabetic nephropathy can eventually lead to nephrotic syndrome (a syndrome characterized by excessive loss of protein in the urine) and chronic renal failure. With the development of end-stage renal disease, the condition usually continues for 2 to 6 years after the onset of renal insufficiency with proteinuria.

The mechanism causing diabetic nephropathy is unknown. It may be caused by inappropriate incorporation of glucose molecules in the basement membrane of the glomerulus and in the structure of the tissue. Hyperfiltration (increased urine production) associated with high blood sugar levels may be an additional mechanism for disease development.

Diabetic nephropathy is the most common cause of chronic kidney failure and end-stage renal disease in the United States. About 40% of people with insulin-dependent diabetes will eventually develop end-stage renal disease. Eighty percent of patients with diabetic nephropathy due to insulin-dependent diabetes mellitus (IDDM) have had this diabetes for 18 years or more. At least 20% of patients with non-insulin-dependent diabetes mellitus (NIDDM) will develop diabetic nephropathy, but the time course of disease development is much more variable than in IDDM. Risks relate to control of blood sugar levels. With poor glucose control, the risk is greater than when glucose levels are well controlled.

Diabetic nephropathy is generally accompanied by other diabetic complications, including hypertension, retinopathy, and vascular changes, although these complications may not be evident in the early stages of nephropathy. Kidney disease can exist for many years before nephrotic syndrome or chronic renal failure develops. Kidney disease is often diagnosed when a routine urinalysis shows protein in the urine.

Current treatment of diabetic nephropathy involves the administration of angiotensin converting enzyme inhibitors (ACE inhibitors) in more advanced stages of the disease. Since ACE inhibitors may not be effective when the disease is asymptomatic (ie, the patient shows only proteinuria), there is currently no treatment for the earlier stages of the disease.

Although hyperglycemia is the mechanism involved in early renal disease in diabetic patients, an underlying mechanism may involve active reabsorption of glucose in the proximal tubule. This reuptake is partly dependent on the adenosine _A1 receptor.

_AAiRA acts on the afferent arterioles of the kidney to produce vasodilation and thus improve renal blood flow in diabetic patients. This ultimately increases GFR and improves kidney function. In addition, _AAiRA inhibits the reabsorption of glucose in the proximal tubules of newly diagnosed diabetic patients or patients at risk of symptoms (metabolic syndrome).

Thus, in one aspect the invention relates to a method of treating diabetic nephropathy comprising determining that a patient is in need of said treatment and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). In certain embodiments, the patient is pre-diabetic, while in other embodiments, the patient is early-stage diabetes. In some embodiments, the patient has insulin-dependent diabetes mellitus (IDDM), while in other embodiments the patient has non-insulin-dependent diabetes mellitus (NIDDM).

In certain embodiments, renal hypertrophy is prevented or reversed using the methods of the invention. In other embodiments, the methods of the invention are used to prevent or reverse renal hyperplasia. In yet other embodiments, the methods of the invention are used to ameliorate microalbuminuria or proteinuria.

Patients almost always have "pre-diabetes" before they develop type 2 diabetes (ie, NIDDM). People with prediabetes have blood sugar levels that are higher than normal but not high enough to be diagnosed as diabetes. For example, a person with prediabetes has blood glucose levels between 110-126 milligrams per deciliter (mg/dL) using the fasting plasma glucose (FPG) test, or between 110 and 126 mg/dL using the oral glucose tolerance test (OGTT). Between 140-200mg/dL. Blood sugar levels below 110 or 140, respectively, were considered normal when using FPG or OGTT, while individuals with blood sugar levels above 126 or 200, respectively, were considered diabetic when using FPG or OGTT. The methods of the present invention can be practiced with any compound that antagonizes the adenosine _A1 receptor.

Certain aspects of the methods of the invention can be practiced using a combination therapy, ie, an _AAiRA compound of the invention is administered to the patient in combination with a second compound. In certain embodiments, the second compound may be selected from protein kinase C inhibitors, tissue proliferation inhibitors, antioxidants, glycation inhibitors, and endothelin B receptor inhibitors.

pharmaceutical composition

The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical ingredients such as diluents or carriers. The pharmaceutical compositions facilitate administration of the compounds to an organism. Various techniques for administering compounds exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like .

The term "carrier" defines a compound that facilitates the incorporation of a compound in cells or tissues. Dimethyl sulfoxide (DMSO), for example, is a commonly used carrier because it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

The term "diluent" defines the class of compounds that are diluted in water, which dissolves the compound of interest and stabilizes the biologically active form of the compound. In this technique, salts dissolved in buffered solutions are used as diluents. Phosphate buffered saline is a commonly used buffer solution because it mimics the saline environment of human blood. Because buffer salts can control the pH of a solution at low concentrations, buffered diluents rarely alter the biological activity of a compound.

The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

The pharmaceutical compositions described herein may be administered to human patients as such or, as in combination therapy, in the form of pharmaceutical compositions mixed with other active ingredients or suitable carriers or excipients. Compounds for immediate use can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA, USA, 1990 formulation and administration techniques.

Suitable routes of administration may include, for example, oral, rectal, transmucosal or enteral administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, also including intrathecal, direct intraventricular, intraperitoneal, Injected intranasally or intraocularly.

Alternatively, the compound may be administered in a local rather than systemic manner, such as by direct injection of the compound, usually in a depot or sustained release formulation, into the renal or cardiac region. In addition, the drug can be administered in a targeted drug delivery system, for example in a liposome encapsulated with tissue-specific antibodies. The liposomes will target and be selectively taken up by the organ.

The pharmaceutical compositions according to the invention can be manufactured in a manner known per se, eg by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

Thus, pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients which facilitate processing of the active compounds into preparations which can be used pharmaceutically. and additives. Proper formulation is dependent on the route of administration chosen. Any suitable and well understood techniques, carriers and excipients known in the art may be used, for example as described in Reye's Encyclopedia of Pharmacy, supra.

For injection, the agents of the invention may be formulated in aqueous solutions or lipid emulsions, preferably in solutions such as Hanks's solution, Ringer's solution or physiological saline buffer. formulated in physiologically compatible buffers. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical combination of the present invention, optionally grinding the resulting mixture and processing it, after adding suitable auxiliaries if necessary The mixture of granules to obtain tablets or dragees. Suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, Methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If necessary, a disintegrant such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

Dragee centers are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers may be added. Additionally, the formulations of the present invention may include enteric polymers. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds used according to the invention are in the form of an aerosol spray using a suitable gas such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Propellants are conveniently delivered from pressurized packs or nebulizers. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of, eg, gelatin, containing a powder mix of the compound and a suitable powder base such as lactose or starch, may be formulated for use in an inhaler or insufflator.

The compounds may be formulated for parenteral administration by injection, eg, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Suspensions may also optionally contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

For example, the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the previously described formulations, the compounds can also be formulated as a depot formulation. Said long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, sparingly soluble salts.

The pharmaceutical carrier for the hydrophobic compound of the present invention is a co-solvent system comprising benzyl alcohol, an anpolar surfactant, a water-miscible organic polymer and an aqueous phase. The general co-solvent system used is the VPD co-solvent system, which is a 3% weight volume ratio (w/v) of benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate (Polysorbate) 80 ^TM and 65% A solution of w/v polyethylene glycol 300, made up to volume with absolute ethanol. Of course, the proportions of the co-solvent system can be varied widely without destroying its solubility and toxicity characteristics. In addition, the co-solvent composition itself can be varied: for example, other less toxic non-polar surfactants can be used instead of POLYSORBATE 80 ^™ ; the fraction size of polyethylene glycol can be varied; other biocompatible polymers can be substituted for poly Glycols such as polyvinylpyrrolidone; and other sugars or polysaccharides can be substituted for dextrose.

Alternatively, other delivery systems can be used for hydrophobic pharmaceutical compounds. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used, although usually at the expense of greater toxicity. Alternatively, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been identified and are well known to those skilled in the art. Depending on the chemical nature of the sustained release capsule, it may release the compound for several weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies can be used for protein stabilization.

Some emulsions useful for dissolving and delivering the xanthine derivatives described above are discussed in US Patent No. 6,210,687, which is incorporated herein by reference in its entirety (including any drawings).

Many of the compounds used in the pharmaceutical combinations of the present invention can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free acid or base forms.

Pharmaceutical compositions suitable for use in the present invention include compositions which contain the active ingredient in an amount effective for its intended purpose. More precisely, a therapeutically effective dose means that dose of the compound effective to prevent, alleviate or ameliorate disease symptoms or prolong survival of the patient being treated. Determination of a therapeutically effective dose is well within the capability of those skilled in the art, particularly in view of the detailed disclosure provided herein.

The exact formulation, route of administration and dosage of the pharmaceutical composition of the present invention can be chosen by the individual physician in consideration of the patient's condition (see, for example, "The Pharmacological Basis of Therapeutics" by Fingl et al., 1975. ") of Chapter 1, page 1). Typically, the dosage of the composition administered to a patient may generally range from about 0.5 to 1000 milligrams per kilogram of patient body weight. A single dose or a series of two or more doses may be administered over the course of one or more days, as desired by the patient.

The daily dosage regimen for adult patients can be: for example, the oral dose of the pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof is between 0.1 mg and 500 mg, preferably between 1 mg and 250 mg, calculated as free base Between, such as 5mg to 200mg or intravenous, subcutaneous or intramuscular doses between 0.01mg to 100mg, preferably between 0.1mg to 60mg, such as 1 to 40mg, daily administration of the composition 1 to 100mg 4 times. Alternatively the composition of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 400 mg per day. Thus, the total daily dose for oral administration should be in the range of 1 to 2000 mg and for parenteral administration should be in the range of 0.1 to 400 mg. Suitably the compound should be administered for a continuous period of treatment, for example a week or more, or months or years.

Dosage amount and dosage interval may be adjusted individually to provide plasma levels or minimum effective concentration (MEC) of the active moiety sufficient to maintain a modulating effect. The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or biological assays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time and optimally 50-90% of the time.

In the case of local administration or selective uptake, the effective local concentration of the drug is independent of the plasma concentration.

The amount of the composition administered will of course depend on the patient being treated, the patient's weight, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

The compositions may, if desired, be presented in a pack or pack containing one or more unit dosage forms containing the active ingredient. For example, the package may comprise metal or plastic foil, such as a blister pack. The pack or dispensing device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a notice pertaining to the container in the form specified by the governmental agency regulating the manufacture, use, or sale of drugs, the notice reflecting the agency's regulations for human or veterinary drug administration. Drug Form Approval. For example, the notice can be a U.S. Food and Drug Administration approved labeling for a prescription drug or an approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, which can be placed in an appropriate container and labeled as indicated for treatment of the condition.

Claims (25)

1. A pharmaceutical composition, characterized in that: said pharmaceutical composition comprises a β-blocker (beta-blocker) and an adenosine A ₁ receptor antagonist (adenosine A ₁ receptor antagonist, AA ₁ RA) . 2. The composition according to claim 1, characterized in that: the beta-blocker is selected from the group consisting of the following: acebutolol hydrochloride (acebutolol hydrochloride), atenolol (atenolol) ), betaxolol hydrochloride, bisoprolol fumarate, carteolol hydrochloride, esmolol hydrochloride, metoprolol , metoprolol tartrate, nadolol, penbutolol sulfate, pindolol, propranolol hydrochloride, succinate and Timolol maleate, or a pharmaceutically acceptable salt, prodrug, ester or amide thereof. 3. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises an angiotensin converting enzyme (ACE) inhibitor and an adenosine A ₁ receptor antagonist (AA ₁ RA). 4. A pharmaceutical composition, characterized in that: the pharmaceutical composition comprises an angiotensin II receptor blocker (angiotensin II receptor blocker, ARB) and an adenosine A ₁ receptor antagonist (AA ₁ RA ). 5. A pharmaceutical composition, characterized in that: said pharmaceutical composition comprises an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB) and an adenosine _A receptor Antibody antagonist (AA ₁ RA). 6. The composition according to claim 3, characterized in that: said ACE inhibitor is selected from the group consisting of: lisinopril (lisinopril), enalapril (enalapril), quinapril Quinapril, ramipril, benazepril, captopril, fosinopril, moexipril, trandolapril (trandolapril) and perindopril (perindopril), or pharmaceutically acceptable salts, prodrugs, esters or amides thereof. 7. The composition according to claim 4, characterized in that: the ARB is selected from the group consisting of the following: losartan (losartan), irbesartan (irbesartan), candesartan ( candesartan), telmisartan, eposartan, and valsartan. 8. The composition according to any one of claims 1, 3 or 4, wherein said AA ₁ RA is a xanthine-derivative compound (xanthine-derivative compound) of formula I or a pharmaceutical compound thereof acceptable salt, in X ₁ and X ₂ each independently represent oxygen or sulfur; Q means: or

Wherein Y represents a single bond or an alkylene group with 1 to 4 carbon atoms, and n represents 0 or 1; R _and R _each independently represent hydrogen, lower alkyl, allyl, propargyl, or hydroxy-substituted, oxygen-substituted or unsubstituted lower alkyl, and _R represents hydrogen or lower alkyl, or R ₄ and R ₅ are the same or different and each represents hydrogen or hydroxyl, and when R ₄ and R ₅ are both hydrogen, at least one of R ₁ and R ₂ is a lower alkyl group substituted by hydroxyl or oxygen, but when Q for , then R ₁ , R ₂ and R ₃ are not methyl at the same time, or wherein said AA ₁ RA is a xanthine epoxy derivative compound of formula II or formula III, or a pharmaceutically acceptable salt thereof,

Wherein R ₆ and R ₇ are the same or different, and can be hydrogen or an alkyl group of 1-4 carbon atoms, R ₈ is oxygen or (CH ₂ ) _1-4 , and n=0-4. 9. The composition according to claim 8, wherein said AA ₁ RA is selected from the group consisting of 8-(noradamantan-3-yl)-1,3-dipropane 1,3-diallyl-8-(3-noradamantanyl)xanthine (1,3-Diallyl-8 -(3-noradamantyl)xanthine), 3-allyl-8-(3-noradamantyl)-1-propargylxanthine (3-allyl-8-(3-noradamantyl)-l-propargylxanthine) , 8-(trans-9-hydroxyl-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine (8-(trans-9-hydroxy-3-tricyclo[3.3 .1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine), 8-(cis-9-hydroxyl-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine (8-(cis-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1,3-dipropylxanthine), 8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^{3, 7} ] nonyl)-1-(2-oxopropyl)-3-propylxanthine (8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-1-( 2-oxopropyl)-3-propylxanthine), 1-(2-hydroxypropyl)-8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-3-propyl yellow Purine (1-(2-hydroxypropyl)-8-(trans-9-hydroxy-3-tricyclo[3.3.1.0 ^3,7 ]nonyl)-3-propylxanthine), and or a pharmaceutically acceptable salt thereof. 10. A method of treating cardiovascular disease, comprising determining a patient in need of said treatment, and administering the pharmaceutical composition according to claim 1 to said patient. 11. The method according to claim 10, wherein the cardiovascular disease is congestive heart failure, hypertension, asymptomatic left ventricular dysfunction or coronary artery disease. 12. The method of claim 10, wherein the patient requires after-load reduction. 13. The method of claim 10, wherein the patient requires additional diuretic therapy or is refractory to diuretic therapy. 14. A method for treating cardiovascular disease or renal disease, characterized by comprising determining a patient in need of the treatment, and administering to the patient the pharmaceutical composition according to any one of claims 3-5. 15. The method of claim 14, wherein the patient suffers from a cardiovascular disease selected from congestive heart failure, hypertension, asymptomatic left ventricular dysfunction, or acute myocardial infarction, or wherein the patients who require afterload reduction, or where diuretic therapy is refractory to such patients. 16. The method according to claim 14, characterized in that: the kidney disease is renal hypertrophy, renal hyperplasia, microalbuminuria, proteinuria, diabetic nephropathy, contrast agent-mediated nephropathy, toxin-induced kidney injury Or oxygen free radical mediated nephropathy. 17. A method of treating alkalosis comprising determining that a patient is in need of said treatment and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). 18. The method according to claim 17, characterized in that: said alkalosis is metabolic alkalosis or respiratory alkalosis. 19. The method of claim 17, wherein the patient has edema, is on diuretic therapy, or suffers from acid loss through the patient's upper gastrointestinal tract. 20. The method according to claim 17, characterized in that: said AA ₁ RA is a xanthine derivative compound of formula I or a pharmaceutically acceptable salt thereof,

in X ₁ and X ₂ each independently represent oxygen or sulfur; Q means:

or

Wherein Y represents a single bond or an alkylene group with 1 to 4 carbon atoms, and n represents 0 or 1; R _and R _each independently represent hydrogen, lower alkyl, allyl, propargyl, or hydroxy-substituted, oxygen-substituted or unsubstituted lower alkyl, and _R represents hydrogen or lower alkyl, or R ₄ and R ₅ are the same or different and each represents hydrogen or hydroxyl, and when R ₄ and R ₅ are both hydrogen, at least one of R ₁ and R ₂ is a lower alkyl group substituted by hydroxyl or oxygen, but when Q for , then R ₁ , R ₂ and R ₃ are not methyl at the same time, or wherein said AA ₁ RA is a xanthine epoxy derivative compound of formula II or formula III, or a pharmaceutically acceptable salt thereof,

Wherein R ₆ and R ₇ are the same or different, and can be hydrogen or a group of alkyl groups with 1 to 4 carbon atoms, R ₈ is oxygen or (CH ₂ ) _1-4 , and n=0-4. 21. A method of treating diabetic nephropathy, comprising determining that a patient is in need of said treatment, and administering to said patient an adenosine _A1 receptor antagonist ( _AA1RA ). 22. The method according to claim 21, wherein the patient is pre-diabetic or early-stage diabetic. 23. The method according to claim 21, characterized in that: said AA ₁ RA is a xanthine derivative compound of formula I or a pharmaceutically acceptable salt thereof, in X ₁ and X ₂ each independently represent oxygen or sulfur; Q means: or

Wherein Y represents a single bond or an alkylene group with 1 to 4 carbon atoms, and n represents 0 or 1; R _and R _each independently represent hydrogen, lower alkyl, allyl, propargyl, or hydroxy-substituted, oxygen-substituted or unsubstituted lower alkyl, and _R represents hydrogen or lower alkyl, or R ₄ and R ₅ are the same or different and each represents hydrogen or hydroxyl, and when R ₄ and R ₅ are both hydrogen, at least one of R ₁ and R ₂ is a lower alkyl group substituted by hydroxyl or oxygen, but when Q for , then R ₁ , R ₂ and R ₃ are not methyl at the same time, or wherein said AA ₁ RA is a xanthine epoxy derivative compound of formula II or formula III, or a pharmaceutically acceptable salt thereof, Wherein R ₆ and R ₇ are the same or different, and can be hydrogen or a group of alkyl groups with 1 to 4 carbon atoms, R ₈ is oxygen or (CH ₂ ) _1-4 , and n=0-4. 24. The method of claim 21, further comprising administering a compound selected from the group consisting of protein kinase C inhibitors, tissue proliferation inhibitors, antioxidants, glycation inhibitors and endothelin B receptor inhibitors. 25. The method of claim 21, wherein said treatment comprises preventing, reversing or ameliorating a disease selected from the group consisting of renal hypertrophy, renal hyperplasia, microalbuminuria and proteinuria.